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Commentaries on both new and classic studies of importance for the treatment of diabetes are posted here monthly.
UKPDS: 10-Year Follow-up
Richard W. Nesto |
Click here to download PowerPoint slides of this commentary. |
Background
The results of the United Kingdom Prospective Diabetes Study (UKPDS) made a significant impact on the management of Type 2 diabetes through the acceptance of intensive glucose therapy. When first published in 1998, the UKPDS findings galvanized the Type 2 diabetes community by showing a significant benefit of intensive therapy, compared with conventional treatment, on microvascular complications including kidney failure and eye disease (UKPDS 33, 1998; UKPDS 34, 1998). Macrovascular risk reduction during the 10-year trial was not statistically significant in the overall population taking a sulfonylurea or insulin as the intensive regimen. However, in the subgroup of obese individuals treated with a metformin regimen, both microvascular and cardiovascular end points were reduced significantly. Intensive glucose control has become the cornerstone of diabetes management in the last decade, but questions related to the benefits and/or risks of more intensive glycaemic control in macrovascular disease have stayed front and center for many research groups, including the UKPDS group (ACCORD, 2008; ADVANCE, 2008; DCCT/EDIC, 2005; Duckworth et al, 2009; Gæde et al, 2003, 2008).
Several important observations emerged about intensive therapy within the past few years. The first was that macrovascular risk reduction from intensive glucose control may take longer to appear than was initially thought. For example, the Epidemiology of Diabetes Interventions and Complications (EDIC) study, an 11-year follow-up of individuals with Type 1 diabetes from the Diabetes Control and Complications Trial (DCCT), found significant macrovascular risk reduction with intensive therapy that had not been evident at the end of the randomized DCCT trial (DCCT/EDIC, 2005). The second emerging concept held that cardiovascular benefits that do appear earlier in therapy can persist or even grow over time. The Steno-2 study noted this effect in its comparison of a multifactorial intervention with conventional therapy in individuals with Type 2 diabetes: gains in cardiovascular risk reduction in the initial randomized portion of the trial were maintained during a 5.5-year follow-up even though treatments directed at coronary heart disease risk reduction had converged. The effect was seen even if intensive glucose targets had not been maintained during follow-up (Gæde et al, 2003, 2008).
In September of 2008, the UKPDS published 10-year follow-up findings that brought new light to the concept of the ‘legacy effect’, or long-term benefit of early intensive control on macrovascular events. The findings strengthened the argument that intensive therapy must start earlier in the natural history of Type 2 diabetes and be maintained if cardiovascular benefits are to be realized.
Methods and Key Results
The original UKPDS enrolled participants who had a new diagnosis of Type 2 diabetes. Between the years 1977 and 1991, a total of 4209 individuals were randomized to either conventional therapy (diet) or intensive therapy for glycaemic control based on sulfonylurea or insulin or, in overweight individuals, metformin. The study was completed in 1997 and reported the following with respect to sulfonylurea/insulin-based intensive therapy (UKPDS 33, 1998):
- 12% relative risk reduction in any diabetes-related end point (P=0.029)
- 25% reduction in microvascular disease (P=0.0099)
- 16% reduction in myocardial infarction (MI) (P=0.052)
- 6% reduction in all-cause mortality (P=0.44)
Intensive therapy with metformin in overweight participants resulted in the following (UKPDS 34, 1998):
- 32% relative risk reduction in any diabetes-related end point (P=0.0023)
- 29% reduction in microvascular disease (P=0.19)
- 39% reduction in MI (P=0.01)
- 36% reduction in all-cause mortality (P=0.011)
In the 10-year follow-up after the conclusion of the randomized portion of the trial, 3277 participants were seen yearly at UKPDS clinics for 5 years. No attempts were made to keep them on their original treatment regimens. During years 6 through 10, follow-up was carried out via questionnaires to participants and their physicians.
Between-group differences (original intensive versus conventional therapy) in mean glycated haemoglobin (HbA1c) disappeared after year 1 of follow-up, and both groups experienced similar HbA1c improvements thereafter. Nevertheless, the apparent advantages of earlier tight control were sustained or became statistically evident over the decade. The findings for sulfonylurea/insulin therapy included:
- 9% relative risk reduction in any diabetes-related end point (P=0.04)
- 24% reduction in microvascular disease (P=0.001)
- 15% reduction in MI (P=0.01)
- 13% reduction in all-cause mortality (P=0.007)
The metformin arm experienced the following:
- 21% relative risk reduction in any diabetes-related end point (P=0.01)
- 16% reduction in microvascular disease (P=0.31)
- 33% reduction in MI (P=0.005)
- 27% reduction in all-cause mortality (P=0.002)
Mortality over the full course of the UKPDS was 44%, with cardiovascular disease (51.5%) and cancer (24.2%) as the leading causes.
Clinical Implications
The foundation for intensive glucose therapy has become more secure with the UKPDS follow-up data. The sheer numbers amassed by the study—a median 17 years of follow-up, 66,000 person-years of observation—provide reassurances about the conclusions related to the benefit of a strategy targeted to more intensive glycaemic control than was recommended at the time of the study. The clinical findings are consistent not only with the DCCT/EDIC and Steno-2 studies, but with the long-held belief that the relationship between macrovascular disease and glycaemia can be exploited to reduce cardiovascular risk.
The UKPDS also advances the idea that cardiovascular protection secondary to more intensive glycaemic control may take time to emerge; thus, glucose control should be started as early as possible in the course of diabetes. Indeed, in numerous presentations, UKPDS authors have stressed the inability to play ‘catch up’ with glucose control once complications have appeared. The disappointing findings from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) may illustrate this point (ADVANCE, 2008). The ADVANCE participants had major diabetes-related vascular disease by the time they initiated intensive therapy, and after 5 years, they showed no evidence of cardiovascular benefits. Similarly, participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, who had pre-existing cardiovascular disease, showed increased mortality after 3.5 years of intensive therapy (ACCORD, 2008). It is possible that longer-term follow-up would reveal cardioprotection even in these high-risk individuals. The UKPDS authors would argue that while glucose control is important, early glucose control may be critical.
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